Polysaccharides are important biological molecules and they have been widely used in the pharmaceutical industry for the prevention and treatment of diseases. For example, capsular polysaccharides have been used for many years in vaccines against capsulated bacteria, such as meningococcus (Neisseria meningitidis), pneumococcus (Streptococcus pneumoniae) and Hib (Haemophilus influenzae type B).
To enhance immunogenicity of these polysaccharides, particularly in children, conjugate vaccines were developed. These comprise a capsular polysaccharide conjugated to a carrier protein [e.g. references 1, 2, 3]. Conjugation can make T-independent antigens into T-dependent antigens.
A problem with many types of polysaccharide is poor stability in water. The stability of polysaccharides in water can depend on the nature of the β-glycosidic bonds joining the saccharide units. Poor stability in water is a result of the O-glycosidic bonds being readily hydrolysed in the presence of acids or glycosidases. The capsular polysaccharide of serogroup A meningococcus is an example of a polysaccharide having poor stability in water.
The stability of polysaccharides is a particular problem in the manufacture of conjugate vaccines. In order to prepare a polysaccharide-protein conjugate, it is necessary to manipulate chemically functional groups on the polysaccharide so that the polysaccharide may be linked to a protein. The exposure of a polysaccharide to chemical reagents in processes for doing this, and particularly to acids, may result in undesirable cleavage of glycosidic linkages and consequent fragmentation of the polysaccharide. Such fragmentation is highly undesirable, causing loss in yields in the synthesis of polysaccharide-protein conjugates.
Polysaccharides which are unstable in this way generally require careful choice of reagents and conditions to circumvent the problems described above. However, this limits the reagents available for manipulating the polysaccharide, thus limiting the range of linkages that may be made between the polysaccharide and carrier protein. In addition, the instability of these polysaccharides means it is difficult to develop robust procedures, which can be used to prepare vaccines on an industrial scale.
Reference 4 discloses a modified capsular saccharide comprising a blocking group at a hydroxyl group position on at least one of the monosaccharide units of the corresponding native capsular saccharide. The modified capsular saccharide is said to have improved stability to hydrolysis. It is an object of the invention to provide alternative or improved modified capsular saccharides that have improved stability to hydrolysis.